doi: 10.1111/jop.12136
J Oral Pathol Med © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jop
REVIEW ARTICLE
Oral lichen planus in Arab countries : a review Lubna Al-Nasser1,2, Ashraf El-Metwally2 1
Dental Services, Central Region Ministry of National Guard, Riyadh, Saudi Arabia; 2Department of Epidemiology and Biostatistics, College of Public Health and Health Informatics, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Oral lichen planus (OLP) is a chronic mucocutaneous inflammatory disease of unknown etiology with a potential for malignant transformation. Little is known about the epidemiology of this condition in the Arab world. A computer-based literature search was conducted using relevant keywords to retrieve studies conducted in Arab world pertaining to OLP, 28 articles were identified initially. After screening for exclusion criteria/retrieving full texts, a total of 15 articles were used for this review. Three studies were cross-sectional and found a prevalence ranging from 0.35% to 1.7%. Studies about risk factors and prognostic markers were conducted in clinical settings, using a case–control design mostly (n = 9), cohort (n = 2), and clinical trial (n = 1). Genetic expressions of various proteins (e.g., BCL family), cultural determinants (Deram chewing), bacterial and viral infections [Helicobacter pylori and Hepatitis C virus (HCV)] were among factors investigated. Evidence extracted from these studies shows a possible link between OLP and Deram use, H. pylori and HCV Infections with a prevalence of the latter infection ranging from 14.7% to 26.3% in patients with OLP. However, paucity of population-based studies limits generalizability of such evidence. Future studies in the Arab world should focus upon surveying the extent of OLP, identifying cultural risk factors, utilization of OLP genetic markers in diagnostic, and prognostic applications. J Oral Pathol Med (2013) Keywords: Arab; epidemiology; oral lichen planus; premalignant; prevalence
Introduction Lichen planus (LP) is a chronic T cell-mediated inflammatory disease of unknown cause that affects oral mucous Correspondence: Lubna Al-Nasser, Dental Services, Central Region (Internal Mail Code 1243), King Abdulaziz Medical City, Ministry of National Guard, P.O. Box 22490, Riyadh 11426, Saudi Arabia Tel: +9661-801-1111 Ext. 14090 or 14061 Fax: +9661-801-1111 Ext. 14010 E-mail: [email protected] Accepted for publication October 10, 2013
membranes, skin, and genitalia (1). Oral lichen planus (OLP) had been classified as premalignant condition by World Health Organization in 1997 (2). It mostly affects middle-aged population over 40, and female sex predilection was observed (3). International studies have given inconsistent data about prevalence of OLP that ranged between 0.06% and 3.2% (4). Recently, consensus seemed to support the potential for malignant transformation of OLP, with a transformation rate from prospective studies ranging from 0.4% to 6.5% (5, 6). It was ventured in some clinical studies that the erosive form of OLP has a higher malignant potential but conclusive evidence is lacking (5). In Arab countries, no review articles have summarized the evidence with respect to the burden and knowledge about determinants of OLP. The present article summarizes OLP studies that had been conducted in the Arab countries in regard to epidemiology, risk factors, and prognostic markers.
Methodology An electronic search was conducted to identify articles in PubMed that met our inclusion criteria. Keywords and Boolean phrases used are presented in Appendix 1. Inclusion criteria were as follows: articles in English language, talking about epidemiology and molecular epidemiology of OLP in any Arab country up to 2012. Case reports/series, randomized clinical trials regarding treatment modalities, articles primarily about cutaneous LP, or oral cancer/ premalignant changes were excluded as well as articles about drug-induced lichenoid eruptions. A total of 28 articles met the inclusion criteria dating back to 1985. Titles and Abstracts were reviewed to scan for exclusion criteria; twelve articles were excluded at this stage. Full texts were then retrieved for 16 articles for careful reading and evaluation. Four more articles were excluded then, leaving twelve articles to be included in the review. A flow chart for the research strategy can be seen in Fig. 1. Secondary research was performed by: Cross-referencing and supplementary electronic search in a number of databases were conducted using a combination of relevant keywords (Appendix 1). Searching local-specialized Journals (published in Arabic or English) in Arab world was
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
2
research within OLP to prevalence studies, risk factors studies, and studies on prognosis or malignant transformation rate. All prevalence studies (n = 4) were conducted in one Arab country and gave a prevalence rate between 0.35 and 1.7% (Table 1). Risk factor studies (n = 8) explored genetic, cultural, viral, and bacterial infections in relation to OLP (Table 2). Prognosis studies (n = 3) investigated factors related to malignant transformation potential of OLP or use of certain markers to diagnose or monitor OLP progression (Table 3).
Discussion
Figure 1 Flowchart for research results from primary and secondary search.
performed as well. The secondary research identified four articles that were not retrieved in our original PubMed search. However, one of these articles was excluded after reading the full text as the study population was sampled from India, although the author’s affiliations were from Saudi Arabia (7).
Results A total of fifteen articles were included in this review. The articles were grouped according to the particular area of
Three prevalence studies were retrieved, point prevalence ranged from 0.35% to 1.7%. Various risk factors were explored in relation to OLP. Genetic determinants that were linked to OLP included COX-2 polymorphisms and apoptosis-related proteins (BCL family). Hepatitis C virus infection and elevated liver enzymes (AST/ALT) were investigated in different populations. Hepatitis C virus prevalence among patients with OLP ranged between 14.7% and 26%. Helicobacter Pylori infection has been detected by PCR in some patients with OLP; however, its role in etiopathology is not yet clarified. Deram chewing was one cultural determinant that had been associated with OLP. Prognostic markers identified from saliva included IFN-c, TNF-a, sTNFR-2. Syndecan-1, p35, p53, and p21 were among genetic protein expressions associated with OLPpositive findings (Table 1). Population prevalence studies were severely lacking in the Arab world, and clinical prevalence studies were conducted in tertiary Dental centers. This might account for high number of cases seen, but it does not reflect OLP prevalence at the population level, as a considerable number of patients maybe self-referred. Moreover, most authors reported that patients with OLP identified were through sequential screening in routine dental examination, which could have missed the symptomatic patients who might have sought treatment elsewhere. Prevalence from the above-mentioned clinical-based studies (0.35–1.7%) fall
Table 1 Oral lichen planus (OLP) prevalence studies Study design/ Sample size/ Population
Histopathologic verification
Saudi Arabia/College of Dentistry, King Saud University Riyadh Saudi Arabia/King Fahad Central Hospital in Gizan, Southern Province
Cross-sectional. 674 dental outpatients
No
Cross-sectional 4277 dental outpatients
Yes
Al-Dosari et al. (9)
Saudi Arabia/ College of Dentistry, King Saud University Riyadh
Cross-sectional. 150 dental outpatients
In Questionable diagnoses
Al-Mobeeriek and Al-Dosari (10)
Saudi Arabia/ College of Dentistry, King Saud University Riyadh
Cross-sectional. 2552 dental outpatients
No
Study Mani (8) Salem (6)
J Oral Pathol Med
Country/setting
Main results Patients screened over 1-year period. OLP point prevalence = 0.6%, equal distribution among males and females. No relation to oral tobacco use was found Dental patients screened over a 5-year period starting 1982. OLP point prevalence was 1.7% (Female 2.02%, Male 1.48%), and majority of cases were symptomatic. OLP cases were followed for an average of 3.2 years and 5.5% developed squamous cell carcinoma at site of oral lesion This study documented clinical presentation of OLP cases seen over the course of 12 years. Females accounted for 53%, age range 41–50 years represented 36% of cases, and reticular type was the commonest 56%, followed by erosive type 26%. Majority of patients had amalgam restorations 68% and 19% of all patients with OLP had diabetes Mellitus Patients screened for the presence of various oral lesions over a 3-year period. OPL point prevalence was 0.35% with a significant male predilection (Male 0.27%, Female 0.08%)
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
3
Table 2 Oral lichen planus (OLP) risk factors studies
Country/setting
Study design/ Sample size/ Population
El-Rifaei et al. (11)
Saudi Arabia/Periodontal Department, Dammam Central Hospital, Eastern Province
Case–control. 34 OLP cases and 32 age-/ gender-matched controls from dental outpatients
Yes
Tonsi and Samdani (12)
Saudi Arabia/ Dermatology Department, Alawi Tonsi Hospital, Makkah
Difficult cases only.
AL-Shawaf and Al-Shawaf (13)
Saudi Arabia/Oral Medicine Clinic, College of Dentistry, Riyadh
Abdel-Latif et al. (14)
Egypt/ Department of Dermatology, Tanta University Hospital and Faculty of Dentistry, Ain Shams University Iraq/ Dermatology department, Basra Teaching hospital
Case–control. 114 cutaneous or patients with OLP and 65 patientrelated healthy volunteers Case–control 40 patients with OLP and 27 age-/ gender-matched controls from dental outpatients Case–control. 25 cutaneous or patients with OLP and 10 age-/ gender-matched controls
Study
Al-Hamdi (15)
Histopathologic verification
Patients with OLP had higher prevalence of both HBVc (7.5%) and HCV (25%) infection, but this relationship was not significant (P value = 0.174)
Yes
Increased caspase-3d expression in LP lesions compared with controls (P = 0.036). Altered Bax expression in suprabasal layers of LP cases compared with controls (P = 0.007). Bcl-2e expression did not show significant differences between LP cases and controls Incidence of OLP among Deram users was 23.3%, women who never used deram had incidence of 1.5% (P < 0.001), relative risk = 27. Vast majority of OLP cases were reticulate type and occurred on Buccal mucosa. Prolonged and frequent chewing of Deram was associated with the highest distribution of OLP H. Pylorig present in gastric mucosa of 45% of patients, equally distributed between both types of OLP patients. Patients with erosive OLP and positive H. Pylori in gastric mucosa had PCR evidence of bacteria presence in oral lesion tissues (P < 0.001) Higher levels of Auto-antibodies to desmogleinh 1 and 3 in OLP cases compared with controls, (P-value = 0.01 and 0.05). Transmission electron microscopic findings show wide gap between basal cells and basal lamina, destruction of cells and desmosomes was evident as well Tissue PGE-2 had significantly higher mean in patients with OLP compared with controls (P < 0.001). PGE-2 levels were significantly different among the three COX-2i genotypes (P < 0.001). Genotype distribution among patients with OLP and controls was comparable
Biopsy for seven cases only
Yes
Egypt/ Dermatology clinic, Ain Shams University Hospital
Ghallab et al. (17)
Egypt/ Department of Oral Medicine, Cairo University
Case–control. 20 patients with erosive OLP and 20 patients with non-erosive OLP matched for age and gender Case–control. 17 erosive patients with OLP and 16 healthy controls
Abdel-Hay et al. (18)
Egypt/ Department of Dermatology and Department of Oral Medicine, Cairo University
Case–control. 50 newly diagnosed atrophic or erosive OLP cases and 50 age- and gendermatched healthy controls
Patients with OLP had significantly higher prevalence of positive anti-HCVa (14.7%) and elevated aminotransferase enzymes (47%) Anti-HCV odds ratio 5.345 (95% CI: 0.589–48.42) and AST/ALTb OR = 27.55 (3.35–225.8) HCV-positive results found in 26% cases and 4.6% in controls (P < 0.001). Only 40% of HCV+ patients were Saudis, the rest belonged to various ethnic groups of south Asia
Difficult cases only
Cohort. 176 women who had the habit of Deramf chewing and 200 women who never chewed Deram
Attia et al. (16)
Main results
Yes
Yes
a
Antibodies to Hepatitis C virus. Aspartate amino-transferase (AST), Alanine amino- transferase (ALT). Hepatitis B virus. d An enzyme in apoptosis-inducing cascade, most specific and early marker of apoptosis. e Bax and Bcl-2: apoptosis regulating proteins. f Deram (Juglans Regia L. bark) is a herbal remedy used by women in Iraq and Gulf countries for cosmetic purposes. It contains naphthoquinone that have irritant properties. g Gram-negative bacterium found in the gastric mucosa. h Desmogliens are transmembrane desmosomal glycoproteins that are important in preserving tissue adhesion. i Cyclooxygenase-2: inducible enzyme in response to inflammatory cytokines. b c
within range acquired from similar international clinical studies (0.01–3.84%) although it tend to be on the lower end. Furthermore, sample size in Saudi studies ranged from 674 to 4277 patients, which was considerably smaller in comparison with some clinical studies in USA, Hungary, and India that screened 14 749,16 322, and 29 448 patients, respectively (22). Another problematic issue is that OLP prevalence was investigated in one country only, Saudi Arabia, which cannot be extrapolated to other countries due to geographical differences in distribution of risk factors. For example, Deram-use features in Gulf countries and Iraq, but it is rather absent in African Arab countries. Similarly, the high
prevalence of HCV in Mediterranean populations can be assumed to affect the strength of association between OLP and HCV when compared to other countries. For instance, prevalence of HCV-positive results in patients with OLP reached up to 26% in the current review, while another review has placed the same prevalence at 4% in Northern France and 62% in a Japanese study (23). Studies that investigated relation of OLP to HCV in this review gave inconsistent results about a significant relation between both diseases. Still, a recent systematic review and meta-analysis showed that patient with LP are significantly more at risk of being seropositive for HCV (Odds ratio 4.85; 95% CI 3.58– 6.56) and that geographical effect of Mediterranean studies J Oral Pathol Med
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
4
Table 3 Studies on oral lichen planus (OLP) malignant transformation
Study
Country/setting
Histopathologic verification
Study design sample SIZE population
Safadi et al. (19)
Jordan/Jordan University of Science and Technology
Case–control. 18 archival specimens of OLP biopsies and 83 control specimens from different categories: (oral mucositis 13, oral focal keratosis 20, oral epithelial dysplasia in mild, moderate, and severe grades 30, normal oral epithelium 10 and 10 oral squamous cell carcinoma)
Yes
Zyada and Fikry (20)
Egypt/ Oral Pathology Department, Mansoura University
Yes
Ghallab et al. (21)
Egypt/ Oral Medicine and Periodontology Clinic, Cairo University
Case–control 43 archival specimens of OLP with a minimum of 2 years followup (subdivided into HCV positive and negative cases) and 20 healthy controls who are HCV negative Clinical study. 20 patients with erosive OLP and 20 age- and gender-matched healthy controls
seemed to increase the odds ratio (24). The same metaanalysis concluded that screening for HCV in patients with OLP is in fact beneficial and might lead to early detection and treatment for HCV. This would also reduce the infection spread from otherwise asymptomatic individuals. Most studies reviewed were case–control studies, conducted at dermatology departments rather than dental departments, which could account for the relatively small number of cases in some studies (i.e., 20 patients). Moreover, controls were either hospital controls or volunteers, which could have introduced a degree of selection bias leading to inflated effect of risk factor. As case–control could be the only practical way to study chronic diseases with low prevalence, sample size calculations should be considered to increase power of study. Appropriate measures of association must be used in interpreting data, such as odds ratio and 95% CI. None of the reviewed studies mentioned sample size calculation or sampling techniques. Future cross-sectional studies should focus on quantifying the extent and magnitude of OLP in Arab countries. Proper sampling on population level should be considered rather than sampling from clinical setting. Case–control studies can be beneficial in identifying behavioral risk factors especially those related to culture-specific practices (e.g., herbal treatments and smokeless tobacco habits). Further clinical studies should elucidate the role of various genetic protein expressions in OLP. Such biomarkers can be enormously important to diagnose OLP or monitor effectiveness of treatment or indicate the malignant potential of OLP. The relation of OLP and HCV should be investigated in Arab countries with respect to the high prevalence of HCV in some geographical areas (e.g., Egypt). Temporality of association of OLP and HCV can be assessed by cohort studies to determine whether OLP can be used to monitor severity of HCV. Erosive type of OLP can be examined by J Oral Pathol Med
Yes
Main results Mean percentage of positive nuclei of P53 in OLP specimens was similar to mild oral epithelial dysplasia, but significantly less than moderate, severe oral epithelial dysplasia, and squamous cell carcinoma. Also, it was significantly higher than mucositis, focal keratosis, and normal epithelium specimens. Mean percentage of positive nuclei of P21 in OLP specimens was lower than moderate, severe dys plasia, and squamous cell carcinoma (P < 0.001) and significantly higher than the rest of control specimens Higher representation of atrophic-erosive OLP in HCV positive compared with HCV negative cases (P < 0.01). Altered syndecan-1 immunoexpression and p35 protein staining were linked to atrophic and erosive forms of OLP (P < 0.01) Salivary IFN-c, TNF-a, and sTNFR-2 were signif icantly higher in patients with OLP before treatment than healthy controls (P = 0.009). After treatment course of systemic prednisone, their levels decreased compared with pre-treatment levels (P ≤ .05)
longitudinal studies as well to relate various clinical and histochemical markers to malignant potential of such lesions.
Conclusion In light of this review, it is obvious that prevalence of OLP needs to be investigated in different geographical locations, and at the population level, with suitable sampling methods to ensure representativeness. Patients with OLP, especially erosive form, should be followed closely for possibility of malignant transformations. A variety of biological markers can be collected by noninvasive methods (i.e., Saliva) for diagnostic and prognostic purposes. Deram, H. Pylori and HCV Infections were among risk factors related to OLP in this review, and prevalence of HCV infection in patients with OLP ranged from 14.7% to 26.3% in studies reviewed. Confirmed diagnosis of OLP can be used as indication to investigate presence of HCV. Still, OLP can benefit greatly from further research in regard to various possible etiologic factors.
References 1. Scully C, Beyli M, Ferreiro MC, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998; 9: 86–122. 2. Ebrahimi M, Nylander K, van der Waal I. Oral lichen planus and the p53 family: what do we know? J Oral Pathol Med 2011; 40: 281–5. 3. Roopashree MR, Gondhalekar RV, Shashikanth MC, George J, Thippeswamy SH, Shukla A. Pathogenesis of oral lichen planus–a review. J Oral Pathol Med 2010; 39: 729–34. 4. Garcia-Pola Vallejo MJ, Martinez Diaz-Canel AI, Garcia Martin JM, Gonzalez Garcia M. Risk factors for oral soft tissue lesions in an adult Spanish population. Commun Dent Oral Epidemiol 2002;30:277–85.
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
5. Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB, Thongprasom K. Current controversies in oral lichen planus: report of an international consensus meeting. Part 2. Clinical management and malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100: 164–78. 6. Salem G. Oral lichen planus among 4277 patients from Gizan, Saudi Arabia. Commun Dent Oral Epidemiol 1989; 17: 322–4. 7. Ali AA, Suresh CS. Oral lichen planus in relation to transaminase levels and hepatitis C virus. J Oral Pathol Med 2007; 36: 604–8. 8. Mani N. Preliminary report on prevalence of oral cancer and precancerous lesions among dental patients in Saudi Arabia. Commun Dent Oral Epidemiol 1985; 13: 2. 9. AlDosari A, Al-Shawaf M, Narter N, Faden A. Clinical Evaluation of 150 Saudi Patients with Lichen Planus. Saudi Dent J 1997; 9: 4. 10. Al-Mobeeriek A, AlDosari AM. Prevalence of oral lesions among Saudi dental patients. Ann Saudi Med 2009; 29: 365–8. 11. El-Rifaei AM, Fathalla SE, Al-Sheikh IH, Tinguria MB, Qadry YA. The prevalence of indices of hepatitis C and B infection, and elevated aminotransferase enzymes in patients with oral lichen planus (olp) in eastern saudi arabia. J Family Community Med 1998;5 39–43. 12. Asaad T, Samdani AJ. Association of lichen planus with hepatitis C virus infection. Ann Saudi Med 2005; 25: 243–6. 13. Al-Shawaf R, Al-Shawaf M. Hepatitis B and C virus infection and oral lichen planus: A report from Saudi Arabia. Saudi Dent J 2006; 8: 5. 14. Abdel-Latif AM, Abuel-Ela HA, El-Shourbagy SH. Increased caspase-3 and altered expression of apoptosis-associated proteins, Bcl-2 and Bax in lichen planus. Clin Exp Dermatol 2009; 34: 390–5. 15. Al-Hamdi KI. Can deram be a cause of oral lichen planus? Saudi Med J 2008; 29: 1028–30. 16. Attia EA, Abdel Fattah NS, Abdella HM. Upper gastrointestinal findings and detection of Helicobacter pylori in patients with oral lichen planus. Clin Exp Dermatol 2010;35:355–60. 17. Ghallab N, Shaker O, Gaafar S, Zayed M, Khater D. Is there a relationship between oral lichen planus and desmogliens? Egypt Dent J 2009; 55: 11. 18. Abdel Hay RM, Fawzy MM, Metwally D, et al. DNA polymorphisms and tissue cyclooxygenase-2 expression in oral lichen planus: a case-control study. J Eur Acad Dermatol Venereol 2012;26:1122–6. 19. Safadi RA, Al Jaber SZ, Hammad HM, Hamasha AA. Oral lichen planus shows higher expressions of tumor suppressor gene products of p53 and p21 compared to oral mucositis. An immunohistochemical study. Arch Oral Biol 2010;55:454–61. 20. Zyada MM, Fikry HE. Immunohistochemical study of syndecan-1 down-regulation and the expression of P35 protein in oral lichen planus: a clinicopathologic correlation with hepatitis C infection in the Egyptian population. Ann Diagn Pathol 2010; 14: 153–61. 21. Ghallab NA, el-Wakeel N, Shaker OG. Levels of salivary IFNgamma, TNF-alfa, and TNF receptor-2 as prognostic markers in (erosive) oral lichen planus. Mediators Inflamm 2010;2010:847632. 22. McCartan BE, Healy CM. The reported prevalence of oral lichen planus: a review and critique. J Oral Pathol Med 2008; 37: 447–53.
23. Al Robaee AA, Al Zolibani AA. Oral lichen planus and hepatitis C virus: is there real association? Acta Dermatovenerol Alp Panonica Adriat 2006;15:14–9. 24. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis. Oral Dis 2010; 16: 601–12.
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Appendix 1 Keywords used in PubMed’s advanced search and secondary research to identify articles. Keywords covered three categories: disease of interest, epidemiological terms, and geographical locations. Boolean phrase (AND) was used to link all three categories of key words. The search in all other databases used basically the disease of interest, epidemiological terms, and the word Arab*.
Oral Lichen Planus Diagnosis, OR Distribution, OR Epidemiology, OR Factor, OR Incidence, OR Odds Pattern, OR Prevalence, OR Prognosis, OR Rate, OR Risk, OR Trend, OR
Algeria, OR Bahrain, OR Comoros, OR Djibouti, OR Egypt, OR Emirate, OR Iraq, OR Jordan, OR Kuwait, OR Lebanon, OR Libya, OR Mauritania, OR Morocco, OR Oman, OR Palestine, OR Qatar, OR Saudi, OR Somalia, OR Sudan, OR Syria, OR
Databases searched The Cochrane Library - www.thecochranelibrary.com National Electronic Library for Health - www.nelh.nhs.uk Evidence Based medicine - www.ebm.bmjjournals.com Clinical Evidence - www.clinicalevidence.com PubMed - www.pubmed.gov Trip database - www.tripdatabase.com Centre for Reviews & Dissemination, University of York - www.york.ac. uk/inst/crd/ Embase - www.embase.com/ Sage Journals- http://online.sagepub.com Wiley online library- http://onlinelibrary.wiley.com www.ebscohost.com http://www.elsevier.com/ www.sciencedirect.com/
J Oral Pathol Med
J Oral Pathol Med © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jop
REVIEW ARTICLE
Oral lichen planus in Arab countries : a review Lubna Al-Nasser1,2, Ashraf El-Metwally2 1
Dental Services, Central Region Ministry of National Guard, Riyadh, Saudi Arabia; 2Department of Epidemiology and Biostatistics, College of Public Health and Health Informatics, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Oral lichen planus (OLP) is a chronic mucocutaneous inflammatory disease of unknown etiology with a potential for malignant transformation. Little is known about the epidemiology of this condition in the Arab world. A computer-based literature search was conducted using relevant keywords to retrieve studies conducted in Arab world pertaining to OLP, 28 articles were identified initially. After screening for exclusion criteria/retrieving full texts, a total of 15 articles were used for this review. Three studies were cross-sectional and found a prevalence ranging from 0.35% to 1.7%. Studies about risk factors and prognostic markers were conducted in clinical settings, using a case–control design mostly (n = 9), cohort (n = 2), and clinical trial (n = 1). Genetic expressions of various proteins (e.g., BCL family), cultural determinants (Deram chewing), bacterial and viral infections [Helicobacter pylori and Hepatitis C virus (HCV)] were among factors investigated. Evidence extracted from these studies shows a possible link between OLP and Deram use, H. pylori and HCV Infections with a prevalence of the latter infection ranging from 14.7% to 26.3% in patients with OLP. However, paucity of population-based studies limits generalizability of such evidence. Future studies in the Arab world should focus upon surveying the extent of OLP, identifying cultural risk factors, utilization of OLP genetic markers in diagnostic, and prognostic applications. J Oral Pathol Med (2013) Keywords: Arab; epidemiology; oral lichen planus; premalignant; prevalence
Introduction Lichen planus (LP) is a chronic T cell-mediated inflammatory disease of unknown cause that affects oral mucous Correspondence: Lubna Al-Nasser, Dental Services, Central Region (Internal Mail Code 1243), King Abdulaziz Medical City, Ministry of National Guard, P.O. Box 22490, Riyadh 11426, Saudi Arabia Tel: +9661-801-1111 Ext. 14090 or 14061 Fax: +9661-801-1111 Ext. 14010 E-mail: [email protected] Accepted for publication October 10, 2013
membranes, skin, and genitalia (1). Oral lichen planus (OLP) had been classified as premalignant condition by World Health Organization in 1997 (2). It mostly affects middle-aged population over 40, and female sex predilection was observed (3). International studies have given inconsistent data about prevalence of OLP that ranged between 0.06% and 3.2% (4). Recently, consensus seemed to support the potential for malignant transformation of OLP, with a transformation rate from prospective studies ranging from 0.4% to 6.5% (5, 6). It was ventured in some clinical studies that the erosive form of OLP has a higher malignant potential but conclusive evidence is lacking (5). In Arab countries, no review articles have summarized the evidence with respect to the burden and knowledge about determinants of OLP. The present article summarizes OLP studies that had been conducted in the Arab countries in regard to epidemiology, risk factors, and prognostic markers.
Methodology An electronic search was conducted to identify articles in PubMed that met our inclusion criteria. Keywords and Boolean phrases used are presented in Appendix 1. Inclusion criteria were as follows: articles in English language, talking about epidemiology and molecular epidemiology of OLP in any Arab country up to 2012. Case reports/series, randomized clinical trials regarding treatment modalities, articles primarily about cutaneous LP, or oral cancer/ premalignant changes were excluded as well as articles about drug-induced lichenoid eruptions. A total of 28 articles met the inclusion criteria dating back to 1985. Titles and Abstracts were reviewed to scan for exclusion criteria; twelve articles were excluded at this stage. Full texts were then retrieved for 16 articles for careful reading and evaluation. Four more articles were excluded then, leaving twelve articles to be included in the review. A flow chart for the research strategy can be seen in Fig. 1. Secondary research was performed by: Cross-referencing and supplementary electronic search in a number of databases were conducted using a combination of relevant keywords (Appendix 1). Searching local-specialized Journals (published in Arabic or English) in Arab world was
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
2
research within OLP to prevalence studies, risk factors studies, and studies on prognosis or malignant transformation rate. All prevalence studies (n = 4) were conducted in one Arab country and gave a prevalence rate between 0.35 and 1.7% (Table 1). Risk factor studies (n = 8) explored genetic, cultural, viral, and bacterial infections in relation to OLP (Table 2). Prognosis studies (n = 3) investigated factors related to malignant transformation potential of OLP or use of certain markers to diagnose or monitor OLP progression (Table 3).
Discussion
Figure 1 Flowchart for research results from primary and secondary search.
performed as well. The secondary research identified four articles that were not retrieved in our original PubMed search. However, one of these articles was excluded after reading the full text as the study population was sampled from India, although the author’s affiliations were from Saudi Arabia (7).
Results A total of fifteen articles were included in this review. The articles were grouped according to the particular area of
Three prevalence studies were retrieved, point prevalence ranged from 0.35% to 1.7%. Various risk factors were explored in relation to OLP. Genetic determinants that were linked to OLP included COX-2 polymorphisms and apoptosis-related proteins (BCL family). Hepatitis C virus infection and elevated liver enzymes (AST/ALT) were investigated in different populations. Hepatitis C virus prevalence among patients with OLP ranged between 14.7% and 26%. Helicobacter Pylori infection has been detected by PCR in some patients with OLP; however, its role in etiopathology is not yet clarified. Deram chewing was one cultural determinant that had been associated with OLP. Prognostic markers identified from saliva included IFN-c, TNF-a, sTNFR-2. Syndecan-1, p35, p53, and p21 were among genetic protein expressions associated with OLPpositive findings (Table 1). Population prevalence studies were severely lacking in the Arab world, and clinical prevalence studies were conducted in tertiary Dental centers. This might account for high number of cases seen, but it does not reflect OLP prevalence at the population level, as a considerable number of patients maybe self-referred. Moreover, most authors reported that patients with OLP identified were through sequential screening in routine dental examination, which could have missed the symptomatic patients who might have sought treatment elsewhere. Prevalence from the above-mentioned clinical-based studies (0.35–1.7%) fall
Table 1 Oral lichen planus (OLP) prevalence studies Study design/ Sample size/ Population
Histopathologic verification
Saudi Arabia/College of Dentistry, King Saud University Riyadh Saudi Arabia/King Fahad Central Hospital in Gizan, Southern Province
Cross-sectional. 674 dental outpatients
No
Cross-sectional 4277 dental outpatients
Yes
Al-Dosari et al. (9)
Saudi Arabia/ College of Dentistry, King Saud University Riyadh
Cross-sectional. 150 dental outpatients
In Questionable diagnoses
Al-Mobeeriek and Al-Dosari (10)
Saudi Arabia/ College of Dentistry, King Saud University Riyadh
Cross-sectional. 2552 dental outpatients
No
Study Mani (8) Salem (6)
J Oral Pathol Med
Country/setting
Main results Patients screened over 1-year period. OLP point prevalence = 0.6%, equal distribution among males and females. No relation to oral tobacco use was found Dental patients screened over a 5-year period starting 1982. OLP point prevalence was 1.7% (Female 2.02%, Male 1.48%), and majority of cases were symptomatic. OLP cases were followed for an average of 3.2 years and 5.5% developed squamous cell carcinoma at site of oral lesion This study documented clinical presentation of OLP cases seen over the course of 12 years. Females accounted for 53%, age range 41–50 years represented 36% of cases, and reticular type was the commonest 56%, followed by erosive type 26%. Majority of patients had amalgam restorations 68% and 19% of all patients with OLP had diabetes Mellitus Patients screened for the presence of various oral lesions over a 3-year period. OPL point prevalence was 0.35% with a significant male predilection (Male 0.27%, Female 0.08%)
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
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Table 2 Oral lichen planus (OLP) risk factors studies
Country/setting
Study design/ Sample size/ Population
El-Rifaei et al. (11)
Saudi Arabia/Periodontal Department, Dammam Central Hospital, Eastern Province
Case–control. 34 OLP cases and 32 age-/ gender-matched controls from dental outpatients
Yes
Tonsi and Samdani (12)
Saudi Arabia/ Dermatology Department, Alawi Tonsi Hospital, Makkah
Difficult cases only.
AL-Shawaf and Al-Shawaf (13)
Saudi Arabia/Oral Medicine Clinic, College of Dentistry, Riyadh
Abdel-Latif et al. (14)
Egypt/ Department of Dermatology, Tanta University Hospital and Faculty of Dentistry, Ain Shams University Iraq/ Dermatology department, Basra Teaching hospital
Case–control. 114 cutaneous or patients with OLP and 65 patientrelated healthy volunteers Case–control 40 patients with OLP and 27 age-/ gender-matched controls from dental outpatients Case–control. 25 cutaneous or patients with OLP and 10 age-/ gender-matched controls
Study
Al-Hamdi (15)
Histopathologic verification
Patients with OLP had higher prevalence of both HBVc (7.5%) and HCV (25%) infection, but this relationship was not significant (P value = 0.174)
Yes
Increased caspase-3d expression in LP lesions compared with controls (P = 0.036). Altered Bax expression in suprabasal layers of LP cases compared with controls (P = 0.007). Bcl-2e expression did not show significant differences between LP cases and controls Incidence of OLP among Deram users was 23.3%, women who never used deram had incidence of 1.5% (P < 0.001), relative risk = 27. Vast majority of OLP cases were reticulate type and occurred on Buccal mucosa. Prolonged and frequent chewing of Deram was associated with the highest distribution of OLP H. Pylorig present in gastric mucosa of 45% of patients, equally distributed between both types of OLP patients. Patients with erosive OLP and positive H. Pylori in gastric mucosa had PCR evidence of bacteria presence in oral lesion tissues (P < 0.001) Higher levels of Auto-antibodies to desmogleinh 1 and 3 in OLP cases compared with controls, (P-value = 0.01 and 0.05). Transmission electron microscopic findings show wide gap between basal cells and basal lamina, destruction of cells and desmosomes was evident as well Tissue PGE-2 had significantly higher mean in patients with OLP compared with controls (P < 0.001). PGE-2 levels were significantly different among the three COX-2i genotypes (P < 0.001). Genotype distribution among patients with OLP and controls was comparable
Biopsy for seven cases only
Yes
Egypt/ Dermatology clinic, Ain Shams University Hospital
Ghallab et al. (17)
Egypt/ Department of Oral Medicine, Cairo University
Case–control. 20 patients with erosive OLP and 20 patients with non-erosive OLP matched for age and gender Case–control. 17 erosive patients with OLP and 16 healthy controls
Abdel-Hay et al. (18)
Egypt/ Department of Dermatology and Department of Oral Medicine, Cairo University
Case–control. 50 newly diagnosed atrophic or erosive OLP cases and 50 age- and gendermatched healthy controls
Patients with OLP had significantly higher prevalence of positive anti-HCVa (14.7%) and elevated aminotransferase enzymes (47%) Anti-HCV odds ratio 5.345 (95% CI: 0.589–48.42) and AST/ALTb OR = 27.55 (3.35–225.8) HCV-positive results found in 26% cases and 4.6% in controls (P < 0.001). Only 40% of HCV+ patients were Saudis, the rest belonged to various ethnic groups of south Asia
Difficult cases only
Cohort. 176 women who had the habit of Deramf chewing and 200 women who never chewed Deram
Attia et al. (16)
Main results
Yes
Yes
a
Antibodies to Hepatitis C virus. Aspartate amino-transferase (AST), Alanine amino- transferase (ALT). Hepatitis B virus. d An enzyme in apoptosis-inducing cascade, most specific and early marker of apoptosis. e Bax and Bcl-2: apoptosis regulating proteins. f Deram (Juglans Regia L. bark) is a herbal remedy used by women in Iraq and Gulf countries for cosmetic purposes. It contains naphthoquinone that have irritant properties. g Gram-negative bacterium found in the gastric mucosa. h Desmogliens are transmembrane desmosomal glycoproteins that are important in preserving tissue adhesion. i Cyclooxygenase-2: inducible enzyme in response to inflammatory cytokines. b c
within range acquired from similar international clinical studies (0.01–3.84%) although it tend to be on the lower end. Furthermore, sample size in Saudi studies ranged from 674 to 4277 patients, which was considerably smaller in comparison with some clinical studies in USA, Hungary, and India that screened 14 749,16 322, and 29 448 patients, respectively (22). Another problematic issue is that OLP prevalence was investigated in one country only, Saudi Arabia, which cannot be extrapolated to other countries due to geographical differences in distribution of risk factors. For example, Deram-use features in Gulf countries and Iraq, but it is rather absent in African Arab countries. Similarly, the high
prevalence of HCV in Mediterranean populations can be assumed to affect the strength of association between OLP and HCV when compared to other countries. For instance, prevalence of HCV-positive results in patients with OLP reached up to 26% in the current review, while another review has placed the same prevalence at 4% in Northern France and 62% in a Japanese study (23). Studies that investigated relation of OLP to HCV in this review gave inconsistent results about a significant relation between both diseases. Still, a recent systematic review and meta-analysis showed that patient with LP are significantly more at risk of being seropositive for HCV (Odds ratio 4.85; 95% CI 3.58– 6.56) and that geographical effect of Mediterranean studies J Oral Pathol Med
Oral lichen planus in Arab countries L Al-Nasser and A El-Metwally
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Table 3 Studies on oral lichen planus (OLP) malignant transformation
Study
Country/setting
Histopathologic verification
Study design sample SIZE population
Safadi et al. (19)
Jordan/Jordan University of Science and Technology
Case–control. 18 archival specimens of OLP biopsies and 83 control specimens from different categories: (oral mucositis 13, oral focal keratosis 20, oral epithelial dysplasia in mild, moderate, and severe grades 30, normal oral epithelium 10 and 10 oral squamous cell carcinoma)
Yes
Zyada and Fikry (20)
Egypt/ Oral Pathology Department, Mansoura University
Yes
Ghallab et al. (21)
Egypt/ Oral Medicine and Periodontology Clinic, Cairo University
Case–control 43 archival specimens of OLP with a minimum of 2 years followup (subdivided into HCV positive and negative cases) and 20 healthy controls who are HCV negative Clinical study. 20 patients with erosive OLP and 20 age- and gender-matched healthy controls
seemed to increase the odds ratio (24). The same metaanalysis concluded that screening for HCV in patients with OLP is in fact beneficial and might lead to early detection and treatment for HCV. This would also reduce the infection spread from otherwise asymptomatic individuals. Most studies reviewed were case–control studies, conducted at dermatology departments rather than dental departments, which could account for the relatively small number of cases in some studies (i.e., 20 patients). Moreover, controls were either hospital controls or volunteers, which could have introduced a degree of selection bias leading to inflated effect of risk factor. As case–control could be the only practical way to study chronic diseases with low prevalence, sample size calculations should be considered to increase power of study. Appropriate measures of association must be used in interpreting data, such as odds ratio and 95% CI. None of the reviewed studies mentioned sample size calculation or sampling techniques. Future cross-sectional studies should focus on quantifying the extent and magnitude of OLP in Arab countries. Proper sampling on population level should be considered rather than sampling from clinical setting. Case–control studies can be beneficial in identifying behavioral risk factors especially those related to culture-specific practices (e.g., herbal treatments and smokeless tobacco habits). Further clinical studies should elucidate the role of various genetic protein expressions in OLP. Such biomarkers can be enormously important to diagnose OLP or monitor effectiveness of treatment or indicate the malignant potential of OLP. The relation of OLP and HCV should be investigated in Arab countries with respect to the high prevalence of HCV in some geographical areas (e.g., Egypt). Temporality of association of OLP and HCV can be assessed by cohort studies to determine whether OLP can be used to monitor severity of HCV. Erosive type of OLP can be examined by J Oral Pathol Med
Yes
Main results Mean percentage of positive nuclei of P53 in OLP specimens was similar to mild oral epithelial dysplasia, but significantly less than moderate, severe oral epithelial dysplasia, and squamous cell carcinoma. Also, it was significantly higher than mucositis, focal keratosis, and normal epithelium specimens. Mean percentage of positive nuclei of P21 in OLP specimens was lower than moderate, severe dys plasia, and squamous cell carcinoma (P < 0.001) and significantly higher than the rest of control specimens Higher representation of atrophic-erosive OLP in HCV positive compared with HCV negative cases (P < 0.01). Altered syndecan-1 immunoexpression and p35 protein staining were linked to atrophic and erosive forms of OLP (P < 0.01) Salivary IFN-c, TNF-a, and sTNFR-2 were signif icantly higher in patients with OLP before treatment than healthy controls (P = 0.009). After treatment course of systemic prednisone, their levels decreased compared with pre-treatment levels (P ≤ .05)
longitudinal studies as well to relate various clinical and histochemical markers to malignant potential of such lesions.
Conclusion In light of this review, it is obvious that prevalence of OLP needs to be investigated in different geographical locations, and at the population level, with suitable sampling methods to ensure representativeness. Patients with OLP, especially erosive form, should be followed closely for possibility of malignant transformations. A variety of biological markers can be collected by noninvasive methods (i.e., Saliva) for diagnostic and prognostic purposes. Deram, H. Pylori and HCV Infections were among risk factors related to OLP in this review, and prevalence of HCV infection in patients with OLP ranged from 14.7% to 26.3% in studies reviewed. Confirmed diagnosis of OLP can be used as indication to investigate presence of HCV. Still, OLP can benefit greatly from further research in regard to various possible etiologic factors.
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5. Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB, Thongprasom K. Current controversies in oral lichen planus: report of an international consensus meeting. Part 2. Clinical management and malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100: 164–78. 6. Salem G. Oral lichen planus among 4277 patients from Gizan, Saudi Arabia. Commun Dent Oral Epidemiol 1989; 17: 322–4. 7. Ali AA, Suresh CS. Oral lichen planus in relation to transaminase levels and hepatitis C virus. J Oral Pathol Med 2007; 36: 604–8. 8. Mani N. Preliminary report on prevalence of oral cancer and precancerous lesions among dental patients in Saudi Arabia. Commun Dent Oral Epidemiol 1985; 13: 2. 9. AlDosari A, Al-Shawaf M, Narter N, Faden A. Clinical Evaluation of 150 Saudi Patients with Lichen Planus. Saudi Dent J 1997; 9: 4. 10. Al-Mobeeriek A, AlDosari AM. Prevalence of oral lesions among Saudi dental patients. Ann Saudi Med 2009; 29: 365–8. 11. El-Rifaei AM, Fathalla SE, Al-Sheikh IH, Tinguria MB, Qadry YA. The prevalence of indices of hepatitis C and B infection, and elevated aminotransferase enzymes in patients with oral lichen planus (olp) in eastern saudi arabia. J Family Community Med 1998;5 39–43. 12. Asaad T, Samdani AJ. Association of lichen planus with hepatitis C virus infection. Ann Saudi Med 2005; 25: 243–6. 13. Al-Shawaf R, Al-Shawaf M. Hepatitis B and C virus infection and oral lichen planus: A report from Saudi Arabia. Saudi Dent J 2006; 8: 5. 14. Abdel-Latif AM, Abuel-Ela HA, El-Shourbagy SH. Increased caspase-3 and altered expression of apoptosis-associated proteins, Bcl-2 and Bax in lichen planus. Clin Exp Dermatol 2009; 34: 390–5. 15. Al-Hamdi KI. Can deram be a cause of oral lichen planus? Saudi Med J 2008; 29: 1028–30. 16. Attia EA, Abdel Fattah NS, Abdella HM. Upper gastrointestinal findings and detection of Helicobacter pylori in patients with oral lichen planus. Clin Exp Dermatol 2010;35:355–60. 17. Ghallab N, Shaker O, Gaafar S, Zayed M, Khater D. Is there a relationship between oral lichen planus and desmogliens? Egypt Dent J 2009; 55: 11. 18. Abdel Hay RM, Fawzy MM, Metwally D, et al. DNA polymorphisms and tissue cyclooxygenase-2 expression in oral lichen planus: a case-control study. J Eur Acad Dermatol Venereol 2012;26:1122–6. 19. Safadi RA, Al Jaber SZ, Hammad HM, Hamasha AA. Oral lichen planus shows higher expressions of tumor suppressor gene products of p53 and p21 compared to oral mucositis. An immunohistochemical study. Arch Oral Biol 2010;55:454–61. 20. Zyada MM, Fikry HE. Immunohistochemical study of syndecan-1 down-regulation and the expression of P35 protein in oral lichen planus: a clinicopathologic correlation with hepatitis C infection in the Egyptian population. Ann Diagn Pathol 2010; 14: 153–61. 21. Ghallab NA, el-Wakeel N, Shaker OG. Levels of salivary IFNgamma, TNF-alfa, and TNF receptor-2 as prognostic markers in (erosive) oral lichen planus. Mediators Inflamm 2010;2010:847632. 22. McCartan BE, Healy CM. The reported prevalence of oral lichen planus: a review and critique. J Oral Pathol Med 2008; 37: 447–53.
23. Al Robaee AA, Al Zolibani AA. Oral lichen planus and hepatitis C virus: is there real association? Acta Dermatovenerol Alp Panonica Adriat 2006;15:14–9. 24. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis. Oral Dis 2010; 16: 601–12.
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Appendix 1 Keywords used in PubMed’s advanced search and secondary research to identify articles. Keywords covered three categories: disease of interest, epidemiological terms, and geographical locations. Boolean phrase (AND) was used to link all three categories of key words. The search in all other databases used basically the disease of interest, epidemiological terms, and the word Arab*.
Oral Lichen Planus Diagnosis, OR Distribution, OR Epidemiology, OR Factor, OR Incidence, OR Odds Pattern, OR Prevalence, OR Prognosis, OR Rate, OR Risk, OR Trend, OR
Algeria, OR Bahrain, OR Comoros, OR Djibouti, OR Egypt, OR Emirate, OR Iraq, OR Jordan, OR Kuwait, OR Lebanon, OR Libya, OR Mauritania, OR Morocco, OR Oman, OR Palestine, OR Qatar, OR Saudi, OR Somalia, OR Sudan, OR Syria, OR
Databases searched The Cochrane Library - www.thecochranelibrary.com National Electronic Library for Health - www.nelh.nhs.uk Evidence Based medicine - www.ebm.bmjjournals.com Clinical Evidence - www.clinicalevidence.com PubMed - www.pubmed.gov Trip database - www.tripdatabase.com Centre for Reviews & Dissemination, University of York - www.york.ac. uk/inst/crd/ Embase - www.embase.com/ Sage Journals- http://online.sagepub.com Wiley online library- http://onlinelibrary.wiley.com www.ebscohost.com http://www.elsevier.com/ www.sciencedirect.com/
J Oral Pathol Med
